Project Summary/Abstract While through efforts like the Surviving Sepsis Campaign, ARDSNet and others, supportive therapies have improved survival of the critically injured and/or septic patient, nonetheless, a substantial number still develop this morbid syndrome and die. Unfortunately, as no true medicinal/ molecular therapeutic agent is presently available to treat the developing immune/ organ dysfunction in these individuals or diagnose/ prognose their trajectory, the need remains to further clarify the complex pathobiology of traumatic shock and/or sepsis so as to identify such agents. In this regard, we have recently uncovered a novel role for a family of cell-associated co-inhibitory receptors, Programmed Cell Death Receptor-1 [PD-1] and B-/T-Lymphocyte Attenuator [BTLA] and their respective ligands, popularly referred to as checkpoint proteins. What our data and information developing in the field tell us is that a number of these receptors may have far more diverse cell/organ targets than those of us historically appreciated. While checkpoint protein expression on CD4/CD8 lymphoid cells has a role in these dysfunctional septic processes, one of the novel observations we have made is that they appear to have unanticipated effects on phagocyte as well as `innate regulatory lymphoid cell' functions that also seems to contribute to the increased susceptibility/ immune suppression in the critically ill injured and/or septic patient/ animal. With this in mind, we propose to examine the following general hypothesis in this MIRA: that the classic co-inhibitory receptor(s), PD-1, BTLA and/or their ligands, play a novel role(s) in regulating the development of shock/septic immune/ organ dysfunction via novel myeloid cell and/or select regulatory lymphoid subset interactions with other immune or non-immune cells present in a given tissue. In the 1st sub-project area we will determine how the select expression of PD-1 or BTLA, on myeloid as opposed to lymphoid cells alters the development of morbid events associated with sepsis; then, how the expression of ligands for these co-inhibitory molecules, on leukocytes and/or endothelial/ epithelial cells, contribute to the onset of septic liver, intestine and/or kidney dysfunction. In our 2nd sub-project area, we will utilize a novel murine model of indirect-acute lung injury (iALI)(dual insults of hemorrhage shock followed by CLP) to ask how checkpoint protein expression not only effect the patho-mechanisms driving the development of iALI, but how are these co-inhibitors altering cell `priming'/'innate immune memory'/function. Finally, (3rd) since the neonate possesses a unique/nave immune system and is more susceptible to morbid response in the face of infectious challenge; we ask if the expression of members of the PD-1 family and/or their ligands not only have a comparative impact on the response to septic insult, but how it might be mediated? To do this we will interrogate these 3 cogent models of sepsis, shock/sepsis and/or neonatal sepsis, by applying a combination genetic mouse models, adoptive transfer and/or chimeric mouse constructs to examine these questions/ hypotheses along with select observational clinical studies in the critical ill patient population.